Our long-term research objectives are to elucidate molecular mechanisms underlying hepatic fibrogenesis, and to search for natural anti-fibrotic agents for the prevention and treatment of this disease. Hepatic stellate cells (HSC) are the major player and primary source of the over-production of extracellular matrix (ECM) during hepatic fibrogenesis. Both of HSC activation and hepatic fibrogenesis are induced by oxidative stress. The GOALS OF THIS PROPOSAL are to elucidate the molecular mechanisms of curcumin in the inhibition of HSC activation and to evaluate the potential of the phyto-chemical in the protection of the liver from fibrogenesis caused by oxidative stress. The OVERALL HYPOTHESIS for this application is that curcumin inhibits HSC activation and protects the liver against fibrogenesis by attenuating oxidative stress, inhibiting HSC cell growth, reducing ECM gene expression and suppressing hepatic inflammation. This overarching hypothesis will be pursued in four Specific Aims. SPECIFIC AIM #1 will study the hypothesis that curcumin inhibits HSC activation by reversing alterations in the expression and the activity of PPAR subtypes, interrupting PDGF and/or EGF signaling, blocking TGF-IS signaling and suppressing CTGF gene expression. SPECIFIC AIM #2 will examine the hypothesis that there exists an antagonistic relationship between PPARgamma expression/activation and TGF-S signaling in HSC, and will further elucidate the underlying molecular mechanisms. SPECIFIC AIM #3 will investigate the hypothesis that the inhibitory effects of curcumin on HSC activation mainly results from its powerful antioxidant capability, i.e. inducing de novo synthesis of glutathione, and will further elucidate the underlying molecular mechanisms. SPECIFIC AIM #4 will test the hypothesis that curcumin protects the liver from fibrogenesis by inhibiting HSC activation and suppressing inflammation through attenuating oxidative stress, reducing production of TNF-a and inhibiting expression of genes relevant to HSC activation and inflammation. This proposal will extensively evaluate effects of curcumin on inhibiting HSC activation and protecting the liver from fibrosis in vitro and in vivo, and will systematically elucidate the underlying molecular mechanisms. Results from this proposal will provide novel insights into the molecular mechanisms of curcumin in the inhibition of HSC activation and a natural anti-fibrotic candidate for the protection of the liver from fibrogenesis without apparent adverse effects.